This study presents a comprehensive in silico pharmacokinetic analysis of 30 novel isatin derivatives designed as potential antibacterial agents. Physicochemical and ADMET parameters were predicted using SwissADME and ADMETlab 2.0, and the relationships between key descriptors were evaluated by Pearson correlation analysis and multiple linear regression. All compounds complied with Lipinski’s Rule of Five. Lipophilicity (logP) showed a strong positive correlation with the volume of distribution (VDss; r = 0.810, p < 0.001) and a moderate positive correlation with plasma protein binding (r = 0.480, p = 0.007), while no significant dependence of systemic clearance on logP or plasma protein binding was observed. Multiple regression analysis identified VDss as the dominant determinant of elimination half-life (β = −1.163, p < 0.001), indicating that distribution-driven processes govern pharmacokinetic variability within this scaffold. The findings provide a rational basis for the optimization of isatin-based compounds with improved ADMET profiles.
Nazir A, Nazir A, Zuhair V, Aman S, Sadiq SUR, Hasan AH, et al. The Global Challenge of Antimicrobial Resistance: Mechanisms, Case Studies, and Mitigation Approaches. Health Sci Rep. 2025 Jul 23;8(7):e71077. doi: 10.1002/hsr2.71077.
Bertagnolio S, Dobreva Z, Centner CM, Olaru ID, Donà D, Burzo S, et al. WHO global research priorities for antimicrobial resistance in human health. Lancet Microbe. 2024 Nov;5(11):100902. doi: 10.1016/S2666-5247(24)00134-4.
Zhang Y, Zheng M, Wang Z, Liu Z, Chen S, Li X, et al. Discovery of novel antibacterial agent for the infected wound treatment: all-hydrocarbon stapling optimization of LL-37. Theranostics. 2024 Jan 20;14(3):1181-1194. doi: 10.7150/thno.87916.
Süssmuth RD, Kulike-Koczula M, Gao P, Kosol S. Fighting Antimicrobial Resistance: Innovative Drugs in Antibacterial Research. Angew Chem Int Ed Engl. 2025 Mar 3;64(10):e202414325. doi: 10.1002/anie.202414325.
Varun, Sonam, Kakkar R. Isatin and its derivatives: a survey of recent syntheses, reactions, and applications. Medchemcomm. 2019 Jan 15;10(3):351-368. doi: 10.1039/c8md00585k.
Kumar G, Singh NP, Kumar K. Recent Advancement of Synthesis of Isatins as a Versatile Pharmacophore: A review. Drug Res (Stuttg). 2021 Mar;71(3):115-121. doi: 10.1055/a-1238-2639.
Liu B, Jiang D, Hu G. The Antibacterial Activity of Isatin Hybrids. Curr Top Med Chem. 2022;22(1):25-40. doi: 10.2174/1568026621666211116090456.
Saleem M, Ahmad M, Mehmood RF, Shaheen A, Qaiser S, Niaz SI, et al. Synthesis of Isatin Derivatives Exhibiting Antibacterial, Antifungal and Cytotoxic Activities. Curr Org Synth. 2022 Aug 6;19(6):748-756. doi: 10.2174/1570179419666220128091313.
De Moraes Gomes PAT, Pena LJ, Leite ACL. Isatin Derivatives and Their Antiviral Properties Against Arboviruses: A Review. Mini Rev Med Chem. 2019;19(1):56-62. doi: 10.2174/1389557518666180424093305.
Cheke RS, Firke SD, Patil RR, Bari SB. ISATIN: New Hope Against Convulsion. Cent Nerv Syst Agents Med Chem. 2018;18(2):76-101. doi: 10.2174/1871524917666171113124112.
Ding Z, Zhou M, Zeng C. Recent advances in isatin hybrids as potential anticancer agents. Arch Pharm (Weinheim). 2020 Mar;353(3):e1900367. doi: 10.1002/ardp.201900367.
Sharma PK, Balwani S, Mathur D, Malhotra S, Singh BK, Prasad AK, et al. Synthesis and anti-inflammatory activity evaluation of novel triazolyl-isatin hybrids. J Enzyme Inhib Med Chem. 2016 Dec;31(6):1520-6. doi: 10.3109/14756366.2016.1151015.
Cheke RS, Patil VM, Firke SD, Ambhore JP, Ansari IA, Patel HM, et al. Therapeutic Outcomes of Isatin and Its Derivatives against Multiple Diseases: Recent Developments in Drug Discovery. Pharmaceuticals (Basel). 2022 Feb 22;15(3):272. doi: 10.3390/ph15030272.
Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022 Jul;12(7):3049-3062. doi: 10.1016/j.apsb.2022.02.002.
Burian A, Wagner C, Stanek J, Manafi M, Böhmdorfer M, Jäger W, et al. Plasma protein binding may reduce antimicrobial activity by preventing intra-bacterial uptake of antibiotics, for example clindamycin. J Antimicrob Chemother. 2011 Jan;66(1):134-7. doi: 10.1093/jac/dkq400.
Yang L, Sunzel M, Xu P, Edeki T, Wilson D, Li J, et al. Evaluation of the pharmacokinetics and safety of single and multiple ceftaroline fosamil infusions in healthy Chinese and Western subjects. Int J Clin Pharmacol Ther. 2015 Aug;53(8):681-91. doi: 10.5414/CP202343.
Wang S, Dong G, Sheng C. Structural simplification: an efficient strategy in lead optimization. Acta Pharm Sin B. 2019 Sep;9(5):880-901. doi: 10.1016/j.apsb.2019.05.004.
Wu F, Zhou Y, Li L, Shen X, Chen G, Wang X, et al. Computational Approaches in Preclinical Studies on Drug Discovery and Development. Front Chem. 2020 Sep 11;8:726. doi: 10.3389/fchem.2020.00726.
Venkataraman M, Rao GC, Madavareddi JK, Maddi SR. Leveraging machine learning models in evaluating ADMET properties for drug discovery and development. ADMET DMPK. 2025 Jun 7;13(3):2772. doi: 10.5599/admet.2772.
Poroikov VV. Komp'iuternoe konstruirovanie lekarstv: ot poiska novykh farmakologicheskikh veshchestv do sistemnoĭ farmakologii [Computer-aided drug design: from discovery of novel pharmaceutical agents to systems pharmacology]. Biomed Khim. 2020 Jan;66(1):30-41. Russian. doi: 10.18097/PBMC20206601030.
Marques L, Costa B, Pereira M, Silva A, Santos J, Saldanha L, et al. Advancing Precision Medicine: A Review of Innovative In Silico Approaches for Drug Development, Clinical Pharmacology and Personalized Healthcare. Pharmaceutics. 2024 Feb 27;16(3):332. doi: 10.3390/pharmaceutics16030332.
Yongye AB, Medina-Franco JL. Systematic characterization of structure-activity relationships and ADMET compliance: a case study. Drug Discov Today. 2013 Aug;18(15-16):732-9. doi: 10.1016/j.drudis.2013.04.002.
Othman B, Beigh S, Albanghali MA, Sindi AAA, Shanawaz MA, Ibahim MAEM, et al. Comprehensive pharmacokinetic profiling and molecular docking analysis of natural bioactive compounds targeting oncogenic biomarkers in breast cancer. Sci Rep. 2025 Feb 13;15(1):5426. doi: 10.1038/s41598-024-84401-4.
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002 Jun 6;45(12):2615-23. doi: 10.1021/jm020017n.
Holt K, Nagar S, Korzekwa K. Methods to Predict Volume of Distribution. Curr Pharmacol Rep. 2019 Oct;5(5):391-399. doi: 10.1007/s40495-019-00186-5.
Wu J, Lorusso PM, Matherly LH, Li J. Implications of plasma protein binding for pharmacokinetics and pharmacodynamics of the γ-secretase inhibitor RO4929097. Clin Cancer Res. 2012 Apr 1;18(7):2066-79. doi: 10.1158/1078-0432.CCR-11-2684.
Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar 3;7:42717. doi: 10.1038/srep42717.
Xiong G, Wu Z, Yi J, Fu L, Yang Z, Hsieh C, et al. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res. 2021 Jul 2;49(W1):W5-W14. doi: 10.1093/nar/gkab255.
Akoglu H. User's guide to correlation coefficients. Turk J Emerg Med. 2018 Aug 7;18(3):91-3. doi: 10.1016/j.tjem.2018.08.001.
Olsen AA, McLaughlin JE, Harpe SE. Using multiple linear regression in pharmacy education scholarship. Curr Pharm Teach Learn. 2020 Oct;12(10):1258-68. doi: 10.1016/j.cptl.2020.05.017.
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